9-132912294-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000368.5(TSC1):c.901C>G(p.Gln301Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q301H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.17

Genes affected

TSC1 (HGNC:12362): (TSC complex subunit 1) This gene is a tumor suppressor gene that encodes the growth inhibitory protein hamartin. The encoded protein interacts with and stabilizes the GTPase activating protein tuberin. This hamartin-tuberin complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. This protein also functions as a co-chaperone for Hsp90 that inhibits its ATPase activity. This protein functions as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients, including TSC2 and thereby preventing their ubiquitination and proteasomal degradation. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TSC1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.901C>G	p.Gln301Glu	missense_variant	9/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.901C>G	p.Gln301Glu	missense_variant	9/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2022

The p.Q301E variant (also known as c.901C>G), located in coding exon 7 of the TSC1 gene, results from a C to G substitution at nucleotide position 901. The glutamine at codon 301 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.;T;.;T;.;T;.;.;.;.;.;.;.;.;.;.;T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.2	M;.;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.95	D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.17	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.
REVEL	Uncertain	0.38
Sift	Benign	0.24	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Sift4G	Benign	0.69	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.
Polyphen		0.29	B;.;B;.;B;.;B;.;.;.;.;P;P;P;.;.;.;P;.
Vest4		0.41
MutPred		0.62		Gain of phosphorylation at Y304 (P = 0.1164);.;Gain of phosphorylation at Y304 (P = 0.1164);Gain of phosphorylation at Y304 (P = 0.1164);Gain of phosphorylation at Y304 (P = 0.1164);Gain of phosphorylation at Y304 (P = 0.1164);Gain of phosphorylation at Y304 (P = 0.1164);Gain of phosphorylation at Y304 (P = 0.1164);Gain of phosphorylation at Y304 (P = 0.1164);.;.;Gain of phosphorylation at Y304 (P = 0.1164);Gain of phosphorylation at Y304 (P = 0.1164);Gain of phosphorylation at Y304 (P = 0.1164);Gain of phosphorylation at Y304 (P = 0.1164);Gain of phosphorylation at Y304 (P = 0.1164);.;Gain of phosphorylation at Y304 (P = 0.1164);.;
MVP		0.77
MPC		0.59
ClinPred		0.87	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-135787681;